Moraxella catarrhalis is an important human respiratory tract pathogen. Approximately 25 million episodes of otitis media occur in children in the US annually; 15 to 20% of these are caused by M. catarrhalis, based on results of cultures of middle ear fluid. Otitis prone children who experience recurrent otitis media suffer from delays in speech and language development as a result of hearing loss. Chronic obstructive pulmonary disease (COPD) is now the fourth most common cause of death in the US and in the world. The course of the disease is characterized by intermittent exacerbations and many of the deaths occur as a result of exacerbations. Approximately half of exacerbations are caused by bacterial infection and M. catarrhalis is the second most common bacterial cause of exacerbations. A vaccine to prevent M. catarrhalis otitis media in children and infections in adults with COPD would have an enormous impact on morbidity and healthcare costs, and in the case of COPD, would reduce mortality. Four antigenically conserved, surface exposed outer membrane proteins have been identified as potential vaccine antigens by work supported by this grant. The overall goal of this proposal is to further evaluate these proteins as vaccine antigens and to use a powerful genomics approach to identify and study additional potential vaccine antigens for M. catarrhalis. In Specific Aim 1, genes that encode surface exposed protein antigens and that are conserved among disease-associated isolates of M. catarrhalis will be identified. In specific Aim 2, the ability of conserved, surface exposed outer membrane proteins to induce potentially protective antibodies will be assessed and the human antibody response to the proteins will be studied. In Specific Aim 3, selected proteins will be evaluated for protection in the mouse pulmonary clearance model. The goal of the work is to identify surface proteins that 1) are conserved among strains, 2) are expressed during human infection, and 3) induce protective immune responses in vitro and in vivo. In addition to identifying vaccine antigens, this work will be lead to elucidation of important information on the antigenic structure of the M. catarrhalis surface, the identification of surface antigens expressed specifically during human infection and critical information about the human immune response to surface antigens of M. catarrhalis.